ABSTRACT The prefrontal cortex (PFC), part of the cortico-striato-thalamo-cortical (CSTC) circuit, is a critical regulator of cognition/executive function and social processes. Disruptions to this circuit and these behavioral domains are often associated with several neuropsychiatric disorders. Despite the debilitating nature of these impairments, the challenge to develop therapies that effectively manage this myriad of deficits remains unmet. Although current therapeutics to treat neuropsychiatric conditions primarily target dopamine receptors (DARs), specifically the D2R, they also interact with other D2 subclass of DARs (D3R, D4R). The D4R is of particular interest as it is expressed at higher levels than the D2R in key PFC neuronal populations. Additionally, some of the more clinically effective agents also exhibit high D4R affinity. However, previous attempts to develop clinically effective therapies targeting the D4R have proved unsuccessful. Intriguingly, these efforts occurred prior to recent advances in our understanding of the concepts of GPCR biased signaling i.e. signaling through G proteins or ?-arrestins, which elicit different cellular and physiological outcomes. This, coupled with the ability to engineer cell specific genetic manipulations and the capacity to interrogate brain neural network function in real time and in response to pharmacological or behavioral manipulations, all provide us with an exciting opportunity to address this important challenge. Our collaborators have recently developed a purely D4R-selective partial agonist (UCSF924), and we have discovered that it exhibits remarkable antipsychotic-like properties in pharmacological and genetic animal models. The objective of this proposal is to provide proof-of-concept that functionally-selective targeting of the D4R is necessary to mitigate both the cognitive/executive function and social impairments observed in neuropsychiatric disorders. This is accomplished in the following Specific Aims. Aim 1: Systematic determination of D4R-mediated signaling in PFC neuronal subtypes. Aim 2: Elucidating the effect of selective D4R signaling in the regulation of neuronal networks. In Aim 1, we will utilize our validated CRISPR/Cas9 intersectional system to selectively and systematically delete D4R or ?-arrestin2 in PFC pyramidal neurons or interneurons, and assess how UCSF924 modulates select behavioral domains. This will be expanded in Aim 2, where our co-investigator?s laboratory will utilize in vivo electrophysiological ensemble recordings to assess how UCSF924 engages neural networks and modulates behavioral outcomes. Addressing these aims will test our central hypothesis that selective targeting of D4R-mediated signaling in key PFC neurons has therapeutic potential. Our proposed work should provide a proof-of-concept for the development of a strategy to correct behavioral domains that are currently refractory to existing therapies.